B02 CARFILZOMIB AND LENALIDOMIDE-BASED THERAPY FOR THE TREATMENT OF PRIMARY PLASMA CELL LEUKEMIA: RESULTS OF THE FINAL ANALYSIS OF THE PROSPECTIVE PHASE 2 EMN12/HOVON-129 STUDY FOR PATIENTS AGED 18-65 YEARS
Authors: N. van de Donk, M.C. Minnema, B. van der Holt, F. Schjesvold, K.L. Wu, A. Capra, A. Broyl, W.W.H. Roeloffzen, A.P.A. Gadisseur, G. Pietrantuono, L. Pour, V. van der Velden, T. Lund, M. Offidani, M. Grasso, L. Giaccone, M. Cavo, T. Silkjaer, J. Caers, S. Zweegman, R. Hajek, R. Benjamin, A. Vangsted, M. Boccadoro, F. Gay, P. Sonneveld, P. Musto
Journal: HemaSphere (2023)

Introduction: Primary plasma cell leukemia (pPCL) is a rare, aggressive plasma cell disorder with poor prognosis. Median PFS for transplant-eligible pts is approx. 9 months. The EMN12/HOVON129 study assessed carfilzomib and lenalidomide in induction, consolidation, and maintenance for pPCL pts. Pts ≥18 years were enrolled, with different treatment for those 18-65 and ≥66 years. Here we report the results for pts 18-65 years. Methods: Inclusion criteria were newly diagnosed pPCL (>2x109/L circulating monoclonal plasma cells or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Main exclusion criteria were severe cardiac or pulmonary dysfunction; and creatinine clearance of <15 ml/min. There were no restrictions based on blood counts. Pts aged 18-65 years received four 28-day induction cycles of carfilzomib-lenalidomide-dexamethasone (KRd; K: 20/36 mg/m2 days 1,2,8,9,15,16; R: 25 mg days 1-21; d: 20 mg days 1,2,8,9,15,16,22,23), tandem ASCT, 4 KRd consolidation cycles, and KR maintenance (K: 27 mg/m2 on days 1,2,15,16; R: 10 mg on days 1-21/28 days) until progression. Pts eligible for allo-SCT could also receive one ASCT, followed by 2 KRd consolidation cycles, reduced-intensity conditioning allo-SCT and KR maintenance. The primary endpoint was PFS, and secondary endpoints were response rate, OS, and toxicity. Results: From Oct 2015 to Aug 2021, we enrolled 36 pts with pPCL aged ≤65 years. Median age was 60 years; 67% had bone disease; WHO performance status was ≥2 in 33% of pts. Pts had a high tumor burden with a median plasma cell percentage in BM of 80%. The median peripheral blood plasma cell count was 4.1x109/L (range 1.6-60.0); median platelet count was 111x109/L (range 20-517); and median eGFR was 54.0 ml/min (range 15.0-123). Pts had high-risk disease: 58% had elevated LDH, and 47% del(17p), 9% t(4;14), 19% t(14;16), 61% gain/ampl(1q); ≥2 high-risk cytogenetic abnormalities were present in 38%; 26% had t(11;14); 17% had extramedullary plasmacytomas; 64% had ISS 3 and 50% revised ISS 3. Response to induction was ≥PR in 72%, ≥VGPR in 64%, and ≥CR in 14%. 24 pts (67%) received HDM/ASCT; 12 pts (33%) underwent second HDM/ASCT; 5 (14%) received allo-SCT after first HDM/ASCT. 18 pts (50%) received maintenance. Best response on protocol was ≥PR in 83%, ≥VGPR in 81% and ≥CR in 50%; 10 (28%) pts achieved MRD-negative (10-5) CR. With a median follow-up of 40.8 months (range 8-2-74.5), median PFS was 15.5 months (95% CI 9.4-38.4); median OS was 28.4 months (95% CI 15.1-not reached – 19 deaths: 14 for disease progression, 4 infections, and 1 cardiac disorder). In exploratory analyses, pts with elevated LDH, t(14;16), and del(17p) had inferior PFS and OS. For pts who underwent first HDM/ASCT, median PFS and OS were 32.9 and 34.1 months from date of ASCT. ≥G3 toxicity rate was 67%, including infections (25%) and cardiovascular disorders (14%). One patient developed a SPM (MDS). As of July 24, 2022, 25 pts (69%) discontinued treatment mainly because of progression, none for treatment-related toxicity. Conclusions: KRd induction provides efficient and rapid disease control, which allows two-thirds of pts to undergo a first course of HDM/ASCT. Toxicity occurred mainly during the first cycle of induction and was manageable. However, median PFS and OS remain low in pPCL compared to MM.